ABSTRACT More than 95% of the Alzheimer?s patients have the sporadic disease. The mechanisms by which sporadic Alzheimer?s disease (AD) develops are not fully understood. Type 2 diabetes mellitus (T2DM) increases the risk of developing AD, suggesting a common mechanism induced by T2DM, leading to AD. Here we show that the expression of the endothelial protein caveolin-1 (Cav-1) is reduced in the MKR diabetic mouse model. Cav-1 expression is progressively lost in endothelial cells as a function of disease deterioration. We provide evidence that loss of Cav-1 is due to increased pro- inflammatory cytokines in the MKR mice. We further show that loss of endothelial Cav- 1 compromises the expression of insulin receptor and the transport of insulin into the brain. In addition, loss of Cav-1 results in reduced hippocampal neurogenesis, impairments in critical neurogenic receptors and upregulation of amyloid precursor protein (APP) in the hippocampus. These alterations are manifested by impaired learning and memory in MKR diabetic mice. This study will test the hypothesis that chronic inflammation associated with T2DM causes progressive endothelial Cav-1 depletion ultimately leading to AD. Aim 1 will determine the effect of Cav-1 depletion on insulin transport and uptake in T2DM mouse models, endothelial-specific conditional Cav-1-/- (Cdh5-CreERT2/Cav-1loxlox) and Cav-1-reconstituted MKR (EC-Cav1- RC/MKR) transgenic mice. Aim 2 will determine the effect of Cav-1 depletion on hippocampal plasticity and neurogenesis in T2DM mouse models. Aim 3 will examine the effect of Cav-1 depletion on APP metabolism, the development of neuropathology and impaired learning and memory in T2DM. Experiments will examine whether reconstitution of Cav-1 in endothelial cells of diabetic mice (EC-Cav1-RC/MKR) will rescue cognitive deficits and attenuate neuropathology. This study will establish a novel mechanism underlying sporadic AD and determine the therapeutic value of intervention in Cav-1 metabolism.